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Research Articles

E-pharmacophore based virtual screening for identification of dual specific PDE5A and PDE3A inhibitors as potential leads against cardiovascular diseases

, , & ORCID Icon
Pages 2302-2317 | Received 31 Dec 2019, Accepted 19 Mar 2020, Published online: 17 Apr 2020

References

  • Ahmad, F., Murata, T., Shimizu, K., Degerman, E., Maurice, D., & Manganiello, V. (2015). Cyclic nucleotide phosphodiesterases: Important signaling modulators and therapeutic targets. Oral Diseases, 21(1), e25–e50. doi:10.1111/odi.12275
  • Beavo, J. A., & Brunton, L. L. (2002). Cyclic nucleotide research – Still expanding after half a century. Nature Reviews Molecular Cell Biology, 3(9), 710–717. doi:10.1038/nrm911
  • Bento, A. P., Gaulton, A., Hersey, A., Bellis, L. J., Chambers, J., Davies, M., Krüger, F. A., Light, Y., Mak, L., McGlinchey, S., Nowotka, M., Papadatos, G., Santos, R., & Overington, J. P. (2014). The ChEMBL bioactivity database: An update. Nucleic Acids Research, 42(D1), D1083–D1090. doi:10.1093/nar/gkt1031
  • Bhatia, M. S., & Sherikar, A. S. (2017). Investigation of phosphodiesterase 5A (PDE5A) inhibitors by pharmacophore modeling, virtual screening and molecular docking approach. Journal of Applied Pharmaceutical Science, 7(9), 38–43. doi:10.7324/JAPS.2017.70905
  • Bobin, P., Belacel-Ouari, M., Bedioune, I., Zhang, L., Leroy, J., Leblais, V., Fischmeister, R., & Vandecasteele, G. (2016). Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective. Archives of Cardiovascular Diseases, 109(6–7), 431–443. doi:10.1016/j.acvd.2016.02.004
  • Boswell-Smith, V., Spina, D., & Page, C. P. (2006). Phosphodiesterase inhibitors. British Journal of Pharmacology, 147(S1), S252–S257. doi:10.1038/sj.bjp.0706495
  • Braga, R. C., & Andrade, C. H. (2013). Assessing the performance of 3D pharmacophore models in virtual screening: How good are they? Current Topics in Medicinal Chemistry, 13(9), 1127–1138. doi:10.2174/1568026611313090010
  • Card, G. L., England, B. P., Suzuki, Y., Fong, D., Powell, B., Lee, B., Luu, C., Tabrizizad, M., Gillette, S., Ibrahim, P. N., Artis, D. R., Bollag, G., Milburn, M. V., Kim, S.-H., Schlessinger, J., & Zhang, K. Y. J. (2004). Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure, 12(12), 2233–2247. doi:10.1016/j.str.2004.10.004
  • Cesarini, V., Pisano, C., Rossi, G., Balistreri, C. R., Botti, F., Antonelli, G., Ruvolo, G., Jannini, E. A., & Dolci, S. (2019). Regulation of PDE5 expression in human aorta and thoracic aortic aneurysms. Scientific Reports, 9(1), 12206. doi:10.1038/s41598-019-48432-6
  • Chan, S., & Yan, C. (2011). PDE1 isozymes, key regulators of pathological vascular remodeling. Current Opinion in Pharmacology, 11(6), 720–724. doi:10.1016/j.coph.2011.09.002
  • Crosswhite, P., & Sun, Z. (2010). Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. Journal of Hypertension, 28(2), 201.
  • da Silva, V. B., Kawano, D. F., Gomes, A. D. S., Carvalho, I., Taft, C. A., & da Silva, C. H. T. D. P. (2008). Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy. The Journal of Physical Chemistry A, 112(38), 8902–8910. doi:10.1021/jp8011969
  • Del Rio, A., Barbosa, A. J. M., Caporuscio, F., & Mangiatordi, G. F. (2010). CoCoCo: A free suite of multiconformational chemical databases for high-throughput virtual screening purposes. Molecular Biosystems, 6(11), 2122–2128. doi:10.1039/c0mb00039f
  • Dixon, S. L., Smondyrev, A. M., Knoll, E. H., Rao, S. N., Shaw, D. E., & Friesner, R. A. (2006). PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. Journal of Computer-Aided Molecular Design, 20(10–11), 647–671. doi:10.1007/s10822-006-9087-6
  • Dror, O., Schneidman-Duhovny, D., Inbar, Y., Nussinov, R., & Wolfson, H. J. (2009). Novel approach for efficient pharmacophore-based virtual screening: Method and applications. Journal of Chemical Information and Modeling, 49(10), 2333–2343. doi:10.1021/ci900263d
  • Ece, A. (2016). e-Pharmacophore mapping combined with virtual screening and molecular docking to identify potent and selective inhibitors of P90 ribosomal S6 kinase (RSK).
  • Ece, A. (2020). Towards more effective acetylcholinesterase inhibitors: A comprehensive modelling study based on human acetylcholinesterase protein–drug complex. Journal of Biomolecular Structure and Dynamics, 38(2), 565–568. doi:10.1080/07391102.2019.1583606
  • Ece, A., & Sevin, F. (2013). The discovery of potential cyclin A/CDK2 inhibitors: A combination of 3D QSAR pharmacophore modeling, virtual screening, and molecular docking studies. Medicinal Chemistry Research, 22(12), 5832–5843.
  • Feil, R., Lohmann, S. M., de Jonge, H., Walter, U., & Hofmann, F. (2003). Cyclic GMP-dependent protein kinases and the cardiovascular system: Insights from genetically modified mice. Circulation Research, 93(10), 907–916. doi:10.1161/01.RES.0000100390.68771.CC
  • Fischmeister, R., Castro, L. R. V., Abi-Gerges, A., Rochais, F., JurevičIus, J., Leroy, J., & Vandecasteele, G. (2006). Compartmentation of cyclic nucleotide signaling in the heart: The role of cyclic nucleotide phosphodiesterases. Circulation Research, 99(8), 816–828. doi:10.1161/01.RES.0000246118.98832.04
  • Foresta, C., Caretta, N., Zuccarello, D., Poletti, A., Biagioli, A., Caretti, L., & Galan, A. (2008). Expression of the PDE5 enzyme on human retinal tissue: New aspects of PDE5 inhibitors ocular side effects. Eye, 22(1), 144–149. p doi:10.1038/sj.eye.6702908
  • Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., Shaw, D. E., Francis, P., & Shenkin, P. S. (2004). Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. Journal of Medicinal Chemistry, 47(7), 1739–1749. doi:10.1021/jm0306430
  • Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., Sanschagrin, P. C., & Mainz, D. T. (2006). Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. Journal of Medicinal Chemistry, 49(21), 6177–6196. doi:10.1021/jm051256o
  • Genheden, S., & Ryde, U. (2015). The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opinion on Drug Discovery, 10(5), 449–461. doi:10.1517/17460441.2015.1032936
  • Ghosh, S., Liu, X., Zheng, Y., & Uckun, F. M. (2001). Rational design of potent and selective EGFR tyrosine kinase inhibitors as anticancer agents. Current Cancer Drug Targets, 1(2), 129–140. doi:10.2174/1568009013334188
  • Greco, E. A., Spera, G., & Aversa, A. (2006). Combining testosterone and PDE5 inhibitors in erectile dysfunction: Basic rationale and clinical evidences. European Urology, 50(5), 940–947. doi:10.1016/j.eururo.2006.06.049
  • Greenwood, J. R., Calkins, D., Sullivan, A. P., & Shelley, J. C. (2010). Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. Journal of Computer-Aided Molecular Design, 24(6–7), 591–604. doi:10.1007/s10822-010-9349-1
  • Gresele, P., Momi, S., & Falcinelli, E. (2011). Anti-platelet therapy: Phosphodiesterase inhibitors. British Journal of Clinical Pharmacology, 72(4), 634–646. doi:10.1111/j.1365-2125.2011.04034.x
  • Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004). Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. Journal of Medicinal Chemistry, 47(7), 1750–1759. doi:10.1021/jm030644s
  • Hambleton, R., Krall, J., Tikishvili, E., Honeggar, M., Ahmad, F., Manganiello, V. C., & Movsesian, M. A. (2005). Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. Journal of Biological Chemistry, 280(47), 39168–39174. doi:10.1074/jbc.M506760200
  • Hashmi, S. K., Afridi, M. B., Abbas, K., Sajwani, R. A., Saleheen, D., Frossard, P. M., Ishaq, M., Ambreen, A., & Ahmad, U. (2007). Factors associated with adherence to anti-hypertensive treatment in Pakistan. PLoS One, 2(3), e280. doi:10.1371/journal.pone.0000280
  • Hillisch, A., Pineda, L. F., & Hilgenfeld, R. (2004). Utility of homology models in the drug discovery process. Drug Discovery Today., 9(15), 659–669. doi:10.1016/S1359-6446(04)03196-4
  • Honma, T., Hayashi, K., Aoyama, T., Hashimoto, N., Machida, T., Fukasawa, K., Iwama, T., Ikeura, C., Ikuta, M., Suzuki-Takahashi, I., Iwasawa, Y., Hayama, T., Nishimura, S., & Morishima, H. (2001). Structure-based generation of a new class of potent Cdk4 inhibitors: New de novo design strategy and library design. Journal of Medicinal Chemistry, 44(26), 4615–4627. doi:10.1021/jm0103256
  • Huang, N., Shoichet, B. K., & Irwin, J. J. (2006). Benchmarking sets for molecular docking. Journal of Medicinal Chemistry, 49(23), 6789–6801. doi:10.1021/jm0608356
  • Huang, Z., & Wong, C. F. (2016). Inexpensive method for selecting receptor structures for virtual screening. Journal of Chemical Information and Modeling, 56(1), 21–34. doi:10.1021/acs.jcim.5b00299
  • Ikeda, Y. (1999). Antiplatelet therapy using cilostazol, a specific PDE3 inhibitor. Thrombosis and Haemostasis, 82(8), 435–438. doi:10.1055/s-0037-1615863
  • Irwin, J. J., & Shoichet, B. K. (2005). ZINC – A free database of commercially available compounds for virtual screening. Journal of Chemical Information and Modeling, 45(1), 177–182.
  • Jacobson, M. P., Friesner, R. A., Xiang, Z., & Honig, B. (2002). On the role of the crystal environment in determining protein side-chain conformations. Journal of Molecular Biology, 320(3), 597–608. doi:10.1016/S0022-2836(02)00470-9
  • Jacobson, M. P., Pincus, D. L., Rapp, C. S., Day, T. J., Honig, B., Shaw, D. E., & Friesner, R. A. (2004). A hierarchical approach to all-atom protein loop prediction. Proteins: Structure, Function, and Bioinformatics, 55(2), 351–367. doi:10.1002/prot.10613
  • Kaptoge, S., Pennells, L., De Bacquer, D., Cooney, M. T., Kavousi, M., Stevens, G., Riley, L. M., Savin, S., Khan, T., Altay, S., Amouyel, P., Assmann, G., Bell, S., Ben-Shlomo, Y., Berkman, L., Beulens, J. W., Björkelund, C., Blaha, M., Blazer, D. G., … Di Angelantonio, E. (2019). World Health Organization cardiovascular disease risk charts: Revised models to estimate risk in 21 global regions. The Lancet Global Health, 7(10), e1332–e1345. doi:10.1016/S2214-109X(19)30318-3
  • Kawatkar, S., Wang, H., Czerminski, R., & Joseph-McCarthy, D. (2009). Virtual fragment screening: An exploration of various docking and scoring protocols for fragments using Glide. Journal of Computer-Aided Molecular Design, 23(8), 527–539. doi:10.1007/s10822-009-9281-4
  • Khalid, R. R., Maryam, A., Fadouloglou, V. E., Siddiqi, A. R., & Zhang, Y. (2019). Cryo-EM density map fitting driven in-silico structure of human soluble guanylate cyclase (hsGC) reveals functional aspects of inter-domain cross talk upon NO binding. Journal of Molecular Graphics and Modelling, 90, 109–119. doi:10.1016/j.jmgm.2019.04.009
  • Koyama, H., Bornfeldt, K. E., Fukumoto, S., & Nishizawa, Y. (2001). Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation. Journal of Cellular Physiology, 186(1), 1–10. doi:10.1002/1097-4652(200101)186:1<1::AID-JCP1012>3.0.CO;2-D
  • Lipinski, C. A. (2004). Lead-and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337–341. doi:10.1016/j.ddtec.2004.11.007
  • Lovell, S., Davis, I., Arendall, W., III, Bakker, P. I. W., Word, J. M., Prisant, M. G., Richardson, J. S., & Richardson, D. C. (2003). Structure validation by Ca geometry: F, C and Cb deviation. Proteins: Structure, Function, and Bioinformatics, 50(3), 437–450. doi:10.1002/prot.10286
  • Loving, K., Salam, N. K., & Sherman, W. (2009). Energetic analysis of fragment docking and application to structure-based pharmacophore hypothesis generation. Journal of Computer-Aided Molecular Design, 23(8), 541–554. doi:10.1007/s10822-009-9268-1
  • Madden, T. (2013). The BLAST sequence analysis tool. In The NCBI handbook [Internet] (2nd ed.). National Center for Biotechnology Information (US).
  • Mahajan, S., Ghosh, S., Sudbeck, E. A., Zheng, Y., Downs, S., Hupke, M., & Uckun, F. M. (1999). Rational design and synthesis of a novel anti-leukemic agent targeting Bruton’s tyrosine kinase (BTK), LFM-A13 [α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl) propenamide]. Journal of Biological Chemistry, 274(14), 9587–9599. doi:10.1074/jbc.274.14.9587
  • Mantsyzov, A. B., Bouvier, G., Evrard-Todeschi, N., & Bertho, G. (2012). Contact-based ligand-clustering approach for the identification of active compounds in virtual screening. Advances and Applications in Bioinformatics and Chemistry: AABC, 5, 61.
  • Maryam, A., Vedithi, S. C., Khalid, R. R., Alsulami, A. F., Torres, P. H. M., Siddiqi, A. R., & Blundell, T. L. (2019). The molecular organization of human cGMP specific phosphodiesterase 6 (PDE6): Structural implications of somatic mutations in cancer and retinitis pigmentosa. Computational and Structural Biotechnology Journal, 17, 378–389. doi:10.1016/j.csbj.2019.03.004
  • Maurice, D. H. (2005). Cyclic nucleotide phosphodiesterase-mediated integration of cGMP and cAMP signaling in cells of the cardiovascular system. Frontiers in Bioscience, 10(1–3), 1221–1228. doi:10.2741/1614
  • Maurice, D. H., Palmer, D., Tilley, D. G., Dunkerley, H. A., Netherton, S. J., Raymond, D. R., Elbatarny, H. S., & Jimmo, S. L. (2003). Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Molecular Pharmacology, 64(3), 533–546. doi:10.1124/mol.64.3.533
  • Mollica, A., Zengin, G., Durdagi, S., Ekhteiari Salmas, R., Macedonio, G., Stefanucci, A., Dimmito, M. P., & Novellino, E. (2019). Combinatorial peptide library screening for discovery of diverse α-glucosidase inhibitors using molecular dynamics simulations and binary QSAR models. Journal of Biomolecular Structure and Dynamics, 37(3), 726–740. doi:10.1080/07391102.2018.1439403
  • Movsesian, M. (2003). Isoform-selective inhibitors and activators of PDE3 cyclic nucleotide phosphodiesterases. Google Patents.
  • Movsesian, M. A. (2002). PDE3 cyclic nucleotide phosphodiesterases and the compartmentation of cyclic nucleotide-mediated signalling in cardiac myocytes. Basic Research in Cardiology, 97(7), 1–I90. doi:10.1007/s003950200035
  • Movsesian, M. A., & Kukreja, R. C. (2011). Phosphodiesterase inhibition in heart failure. In S. Francis, M. Conti, & M. Houslay (Eds.), Phosphodiesterases as drug targets (pp. 237–249). Springer.
  • Mysinger, M. M., Carchia, M., Irwin, J. J., & Shoichet, B. K. (2012). Directory of useful decoys, enhanced (DUD-E): Better ligands and decoys for better benchmarking. Journal of Medicinal Chemistry, 55(14), 6582–6594. doi:10.1021/jm300687e
  • Nankervis, J. L., Feil, S. C., Hancock, N. C., Zheng, Z., Ng, H.-L., Morton, C. J., Holien, J. K., Ho, P. W. M., Frazzetto, M. M., Jennings, I. G., Manallack, D. T., John Martin, T., Thompson, P. E., & Parker, M. W. (2011). Thiophene inhibitors of PDE4: Crystal structures show a second binding mode at the catalytic domain of PDE4D2. Bioorganic and Medicinal Chemistry Letters, 21(23), 7089–7093. doi:10.1016/j.bmcl.2011.09.109
  • Poli, G., Dimmito, M. P., Mollica, A., Zengin, G., Benyhe, S., Zador, F., & Stefanucci, A. (2019). Discovery of novel µ-opioid receptor inverse agonist from a combinatorial library of tetrapeptides through structure-based virtual screening. Molecules, 24(21), 3872. doi:10.3390/molecules24213872
  • Prabhu, S. V., & Singh, S. K. (2019). Energetically optimized pharmacophore modeling to identify dual negative allosteric modulators against group I mGluRs in neurodegenerative diseases. Journal of Biomolecular Structure and Dynamics, 1–12. doi:10.1080/07391102.2019.1640794
  • Rabe, K., Magnussen, H., & Dent, G. (1995). Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. European Respiratory Journal, 8(4), 637–642.
  • Rosengren, A., Smyth, A., Rangarajan, S., Ramasundarahettige, C., Bangdiwala, S. I., AlHabib, K. F., Avezum, A., Bengtsson Boström, K., Chifamba, J., Gulec, S., Gupta, R., Igumbor, E. U., Iqbal, R., Ismail, N., Joseph, P., Kaur, M., Khatib, R., Kruger, I. M., Lamelas, P., … Yusuf, S. (2019). Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: The Prospective Urban Rural Epidemiologic (PURE) study. The Lancet Global Health, 7(6), e748–e760. doi:10.1016/S2214-109X(19)30045-2
  • Roth, G. A., Johnson, C., Abajobir, A., Abd-Allah, F., Abera, S. F., Abyu, G., Ahmed, M., Aksut, B., Alam, T., Alam, K., Alla, F., Alvis-Guzman, N., Amrock, S., Ansari, H., Ärnlöv, J., Asayesh, H., Atey, T. M., Avila-Burgos, L., Awasthi, A., … Murray, C. (2017). Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. Journal of the American College of Cardiology, 70(1), 1–25. doi:10.1016/j.jacc.2017.04.052
  • Salam, N. K., Nuti, R., & Sherman, W. (2009). Novel method for generating structure-based pharmacophores using energetic analysis. Journal of Chemical Information and Modeling, 49(10), 2356–2368.
  • Sampson, L., Hinton, J., & Garland, C. (2001). Evidence for expression and function of phosphodiesterase type 5 (PDE-V) in rat resistance arteries. British Journal of Pharmacology, 132(1), 13–17. doi:10.1038/sj.bjp.0703831
  • Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., & Sherman, W. (2013). Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. Journal of Computer-Aided Molecular Design, 27(3), 221–234. doi:10.1007/s10822-013-9644-8
  • Saxena, S., Abdullah, M., Sriram, D., & Guruprasad, L. (2018). Discovery of novel inhibitors of Mycobacterium tuberculosis MurG: Homology modelling, structure based pharmacophore, molecular docking, and molecular dynamics simulations. Journal of Biomolecular Structure and Dynamics, 36(12), 3184–3198. doi:10.1080/07391102.2017.1384398
  • Scapin, G., Patel, S. B., Chung, C., Varnerin, J. P., Edmondson, S. D., Mastracchio, A., Parmee, E. R., Singh, S. B., Becker, J. W., Van der Ploeg, L. H. T., & Tota, M. R. (2004). Crystal structure of human phosphodiesterase 3B: Atomic basis for substrate and inhibitor specificity. Biochemistry, 43(20), 6091–6100. doi:10.1021/bi049868i
  • Shivakumar, D., Williams, J., Wu, Y., Damm, W., Shelley, J., & Sherman, W. (2010). Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. Journal of Chemical Theory and Computation, 6(5), 1509–1519. doi:10.1021/ct900587b
  • Sindhikara, D., Spronk, S. A., Day, T., Borrelli, K., Cheney, D. L., & Posy, S. L. (2017). Improving accuracy, diversity, and speed with prime macrocycle conformational sampling. Journal of Chemical Information and Modeling, 57(8), 1881–1894. doi:10.1021/acs.jcim.7b00052
  • Stoclet, J.-C., Keravis, T., Komas, N., & Lugnier, C. (1995). Section review: Cardiovascular & renal: Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases. Expert Opinion on Investigational Drugs, 4(11), 1081–1100. doi:10.1517/13543784.4.11.1081
  • Truchon, J.-F., & Bayly, C. I. (2007). Evaluating virtual screening methods: Good and bad metrics for the “early recognition” problem. Journal of Chemical Information and Modeling, 47(2), 488–508. doi:10.1021/ci600426e
  • Tsai, L.-C L., & Beavo, J. A. (2011). The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. Current Opinion in Pharmacology, 11(6), 670–675. doi:10.1016/j.coph.2011.09.003
  • ul Qamar, M. T., Maryam, A., Muneer, I., Xing, F., Ashfaq, U. A., Khan, F. A., Anwar, F., Geesi, M. H., Khalid, R. R., Rauf, S. A., & Siddiqi, A. R. (2019). Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus. Scientific Reports, 9(1), 1433. doi:10.1038/s41598-018-38450-1
  • UniProt: The universal protein knowledgebase. (2016). Nucleic Acids Research, 45(D1), D158–D169.
  • Vankayalapati, H., Bearss, D. J., Saldanha, J. W., Muñoz, R. M., Rojanala, S., Von Hoff, D. D., & Mahadevan, D. (2003). Targeting aurora2 kinase in oncogenesis: A structural bioinformatics approach to target validation and rational drug design. Molecular Cancer Therapeutics, 2(3), 283–294.
  • Villoutreix, B. O., Eudes, R., & Miteva, M. A. (2009). Structure-based virtual ligand screening: Recent success stories. Combinatorial Chemistry & High Throughput Screening, 12(10), 1000–1016. doi:10.2174/138620709789824682
  • Wang, G., Liu, Z., Chen, T., Wang, Z., Yang, H., Zheng, M., Ren, J., Tian, G., Yang, X., Li, L., Li, J., Suo, J., Zhang, R., Jiang, X., Terrett, N. K., Shen, J., Xu, Y., & Jiang, H. (2012). Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5. Journal of Medicinal Chemistry, 55(23), 10540–10550. doi:10.1021/jm301159y
  • Wang, H., Liu, Y., Huai, Q., Cai, J., Zoraghi, R., Francis, S. H., Corbin, J. D., Robinson, H., Xin, Z., Lin, G., & Ke, H. (2006). Multiple conformations of phosphodiesterase-5: Implications for enzyme function and drug development. Journal of Biological Chemistry, 281(30), 21469–21479. doi:10.1074/jbc.M512527200
  • Wang, H., Ye, M., Robinson, H., Francis, S. H., & Ke, H. (2008). Conformational variations of both phosphodiesterase-5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Molecular Pharmacology, 73(1), 104–110. doi:10.1124/mol.107.040212
  • Wharton, J., Strange, J. W., Møller, G. M. O., Growcott, E. J., Ren, X., Franklyn, A. P., Phillips, S. C., & Wilkins, M. R. (2005). Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. American Journal of Respiratory and Critical Care Medicine, 172(1), 105–113. doi:10.1164/rccm.200411-1587OC
  • Wobst, J., Kessler, T., Dang, T. A., Erdmann, J., & Schunkert, H. (2015). Role of sGC-dependent NO signalling and myocardial infarction risk. Journal of Molecular Medicine, 93(4), 383–394. doi:10.1007/s00109-015-1265-3
  • Workbench, C. G. v3.6. (2010). Now new version can be available at http://www.clcbio.com/products/clcgenomicsworkbench
  • Zhang, W., & Colman, R. W. (2000). Conserved amino acids in metal-binding motifs of PDE3A are involved in substrate and inhibitor binding. Blood, 95(11), 3380–3386. doi:10.1182/blood.V95.11.3380.011k25_3380_3386
  • Zhang, W., Ke, H., & Colman, R. (2002). Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis. Molecular Pharmacology, 62(3), 514–520. doi:10.1124/mol.62.3.514
  • Zhang, W., Ke, H., Tretiakova, A. P., Jameson, B., & Colman, R. W. (2001). Identification of overlapping but distinct cAMP and cGMP interaction sites with cyclic nucleotide phosphodiesterase 3A by site-directed mutagenesis and molecular modeling based on crystalline PDE4B. Protein Science, 10(8), 1481–1489. doi:10.1110/ps.6601

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